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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
A novel therapeutic strategy targeting multiple members
of the γc-family cytokines; principles, relevance and potentially
broad clinical applications.
Authors:
Abstract
Yutaka Tagaya
1
2
Nazli Azimi
Affiliations:
1
Cell Biology Lab, Division of
Basic Science, Institute of Human
Virology, University of Maryland
School of Medicine, Baltimore
MD 21201
2
BIONIZ Therapeutics, Irvine,
CA
Corresponding author:
Yutaka Tagaya
E-mail:
[email protected]
Cytokines play diverse roles in normal and
abnormal immunity. Dysregulated production of
cytokines underlies a variety of disorders in
humans by causing improper immune responses.
Intervention to such abnormal cytokine action has
been utilized in the clinical field as "anti-cytokine
therapy" and proven effective as treatments.
However the current anti-cytokine approaches lack
effective and safe options for treating human
diseases involving more than two cytokines as the
pathogenic reason. This is an issue as the list of
multi-cytokine diseases is expanding. To address
this, a novel technology was developed by
generating a novel class of multi-cytokine
inhibitors (MCI). In short, cytokine-mimetic
peptides were rationally designed each of which
contains a motif shared only by the cytokines of
the target and tested using specific biological assay.
Peptides showing desired antagonistic activity
were screened further for target specificity. The
lead MCI, BNZ 132-1, specifically inhibits IL-2, -9
and -15 while it does not affect other γc-cytokines
(IL-4, -7. and -21) or non-γc cytokines. This design
ensures safety of the peptide upon clinical use by
limiting off-target effects to the minimum, unlike
small-molecule Jak kinase inhibitors which
suppress a diverse array of cytokines and cause
multiple adverse effects. Currently, we are
conducting clinical trials involving BNZ 132-1 and
saw expected transient decrease of select subsets of
lymphocytes with minimum toxicity. BNZ 132-1
may provide a novel opportunity for treating many
diseases such as myelopathy caused by human Tcell leukemia virus-1 (HTLV-1), non-viral human
T-cell malignancies, autoimmunity (Alopecia
areata, rheumatoid arthritis), graft-versus-host
disease (GvH) upon transplant and cytokine release
syndromes post microbial infections.
Copyright 2017 KEI Journals. All Rights Reserved
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
Introduction.
In the following sections, we will:
1. describe the basic nature of the
γc-cytokines and their receptor which are
primary therapeutic targets for us.
2. discuss about an emerging
concept of "multi-cytokine diseases" in
which functionally redundant cytokines
from a single family are pathogenically
involved.
3. overview the currently available
anti-cytokine strategy in the context of
treating multi-cytokine diseases, which
involves the special discussion on the
limitations of current anti-cytokine strategy.
4. present our new BNZ technology
and elaborate on the underlying concept, in
vitro proof-of-concept data, its potential
applications, preclinical data and on the ongoing clinical trial involving the BNZ 132-1
peptide, the lead compound from our new
technology.
1. The γc-family cytokines.
Since these are the intervention targets
of our interest, we will quickly review the
intriguing characteristics of this family of
cytokines, as the function and receptor
configuration of these cytokines directly
connect with the objective, challenges and
the uniqueness of our endeavor.
The composition of multi-subunit receptors for γc-cytokines is depicted. In this family, IL-2 and
IL-15 form a subfamily of their own and the receptor configuration (three subunits instead of
two) illustrates the uniqueness of the subfamily. The α chains for IL-2 and IL-15 are not a
signaling subunit, but mediate the unique trans-presentation for IL-15 (66). In the cascade of
ligand to intracellular signaling components, the γc and Jak3 are the point of conversion and
targeting these molecules is the logical choice to block multiple γc-cytokines by a single agent.
Copyright 2017 KEI Journals. All Rights Reserved
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
Cytokines are small polypeptides
(Molecular weight ranging from 5 to 40kDa)
that induce activation and differentiation of
various hematopoietic cells (1, 2). Most, if
not all, cytokines assume a distinct topology
called "the four-helix bundles" structure (1)
and the γc-family cytokines, namely IL-2, -4,
-7, -9, -15 and -21, belong to this group. All
γc-cytokines use the common gamma (γc,
CD132) as a subunit in their multicomponent receptor systems. Since γc is a
signal transducing molecule, these cytokines
naturally possess overlapping signaling
pathways and display functional redundancy.
The physiologic roles of each cytokine have
been elucidated in detail using genetargeting (Knock-out or KO) and
transgenesis technologies in mice (3-19).
Basically all 6 γc-cytokines are required for
preparing various types of immune cells and
participate in dictating the proper direction
of the immune response upon microbial
invasion and from other causes, as their
biological relevance is well demonstrated by
the phenotype of mice defective of the
shared γc-receptor which have no T, B, NK
cells and manifest severe immunodeficiency
(20, 21) . We have a long history of studying
the mechanisms, receptors, and biological
functions of γc-cytokines because of our
interest in the activation and development of
T and NK cells.
2. Why blocking multiple-cytokines
is a unique and worthy scientific goal?
2-a. Human diseases caused by more
than two cytokines (multi-cytokine
diseases); Though cytokines belonging to
the same family show functional redundancy,
each cytokine has diverse unique functions
(called the pleiotropic nature). Uncontrolled
production or the lack of a cytokine leads to
pathogenic conditions as demonstrated by
the phenotypes of cytokine knock-out or
transgenic mice. In humans, there are many
examples of diseases caused by the
Copyright 2017 KEI Journals. All Rights Reserved
abnormal functioning of cytokine (cytokine
diseases). Anti-cytokine therapy has been
long developed to treat cytokine diseases.
However, we conducted a literature search
and noted that quite a few cytokine diseases
involve more than two cytokines (and very
likely those belonging to the same family)
(22) and that the current anti-cytokine
strategy has limitations in dealing with
cytokine diseases involving multiple
cytokines (22), which prompted us to design
and develop a unique group of cytokine
inhibitors which can block more than two
cytokines for treating such multi-cytokine
diseases. One example of multi-cytokine
diseases is a myelopathy associated with
HTLV-1 (human T-cell leukemia virus 1)
called HAM/TSP (HTLV-1 associated
myelopathy/tropical spastic paraparesis)
(23, 24). HAM/TSP is a progressive and
chronic disease of the spinal cord seen in
0.3~0.5% of HTLV-1 infected individuals,
manifesting painful stiffness and weakness
of the legs. In HAM/TSP patients, T
lymphocytes which cause pathogenesis cross
the blood-brain barrier and damage the
spinal cord by the production of
proinflammatory factors and by the direct
cytotoxic action. As we showed in our
publications, T cells are constitutively
activated in vivo in these patients and
spontaneously proliferate when they were
transferred to ex vivo culture without the
addition of mitogens or cytokines (25, 26).
We later discovered that two γc-cytokines,
namely IL-2 and IL-15 are transcriptionally
activated by the HTLV-1, and cause the
autocrine proliferation and activation of
CD8 T cells, a process likely leading to the
tissue damage in HAM/TSP. We also
demonstrated that both IL-2 and IL-15 need
to be blocked in order to subside the
pathogenic activation of T cells from
HAM/TSP patients (22, 27-30). Examples of
multi-cytokine disease are increasing in
number. There are more examples of multicytokine diseases. To name a few,
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
rheumatoid arthritis which may involve
IL-15, -21, -6, and -7 as pathogenic factors
(31-33) and Celiac Disease which may
involve IL-2, -10, -15 and -21 (34-41). Coproduction of cytokines belonging to a
family may not be too rare. It is reasonable
to assume that cytokines belonging to a
family evolved through gene duplication (of
the cytokine and of the receptor subunits)
and thus the regulatory mechanisms still
share common elements. We use IL-2 and
IL-15 as an example to look into this. IL-15
and IL-2 form a subfamily in the γccytokine family because they share another
signaling subunit, IL-2R/IL-15Rβ (CD122)
in addition to the γc (Figure 1). Despite the
functional similarities between IL-2 and
IL-15, their production seems strictly
separated from each other under normal
circumstances. IL-2 is almost exclusively
produced by T cells as was demonstrated in
an IL-2/GFP knock-in mouse (42) whereas
IL-15 is produced by activated monocytes,
dendritic cells, and stromal cells (43, 44).
Yet, their promoter regions share a few
motifs including the one for NFkB (45),
accounting for the fact that Toll-like
receptor stimulation in monocytes lead to
the production of IL-15 by monocytes and
T-cell activation results in production of
IL-2 by T cells through the activation of the
NFkB pathway. Moreover, the coproduction of IL-2 and -15 in HAM/TSP
seems to involve the transcriptional
activation of these two genes by the transactivator Tax of HTLV-1 (45) through the
activation of the NFkB pathway. Therefore,
it may not be surprising that IL-2 and IL-15
are simultaneously produced from different
cells through an overlapping molecular
mechanism, in particular under pathological
conditions. This would apply to the coproduction of multiple cytokines belonging
to the same family.
Copyright 2017 KEI Journals. All Rights Reserved
2-b. A pitfall - neutralization of one
of the factors in a multi-cytokine disease
may not show visible effects even though
the factor is pathogenically involved;
After identifying that a human disease
belongs to the category of cytokine disease,
the logical strategy is to follow a
reductionist approach; To gather information
to identify the suspect cytokine and to test if
neutralization of the target cytokine would
effectively block the pathogenic signs
associated with the disease. Even if the
involvement of multiple factors was
anticipated, the intuitive assumption is that
the blockade of "a major factor" should have
visible impacts. However this intuition may
be misleading. We have shown this in our
recent publication (22) but will discuss it
here as it is a critical point of our argument;
If two functionally redundant cytokines
(IL-2 and IL-15 on T or NK cells is a perfect
example) are stimulating the target cells as a
1:1 mixture, how much of the biological
activity will be neutralized when only
neutralizing anti-IL-2 or anti-IL-15 antibody
(Ab) was added? The intuitive answer would
be "a 50% inhibition". However, this is not
true at some circumstances, because the
biological response of a cell is not always
linear to the dose of cytokine. The doseresponse relationship follows a sigmoidcurve. At the near-saturating dose,
additional increase of the stimulant no
longer guarantees visible increase of the
response. In reversal, anti-IL-2 antibody
added to a mixture of 0.5 nM each of IL-2
and IL-15 to PHA-activated human T
lymphocytes (which responds to both
cytokines at high affinity; ~50 pM) would
bring down the 100% response of the cells
only to 90~95% (Figure 2). This was
experimentally verified in our previous
publication (22). The important take-homemessage is that the "lack of a visible
inhibition" using an antibody to one
cytokine when more than two cytokines are
cooperating to cause cellular activation does
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
not allow to eliminate the target cytokine
from the equation. In other words, no visible
inhibition does not mean no participation
of the target cytokine. This may become
more critical in vivo because it is difficult to
know how many cytokines are in operation
and how much is the contribution by each
involved cytokine. For example, if cytokine
A was highly suspected in the cause of a
disease but antibody therapy targeting
cytokine A failed. There might have been an
example of this scenario in the actual
clinical trials involving Asthma. Asthma has
been connected to multiple cytokines
including IL-4, IL-13, IL-9, and IL-5 in
previous studies (16, 46-54). Accordingly,
clinical trials involving anti-IL-4 and antiIL-9 therapy have been approved but
separately conducted (47, 48, 55-57).
Unfortunately, neither gave rise to a
satisfactory therapeutic result. This may
simply mean that other cytokines are equally
participating in the cause of the disease thus
a co-inhibition of both factors could be a
"simple" solution.
However,
the
implementation of this strategy may not be
as simple as it may look like.
On the left shown is a typical proliferative response of mitogen-activated T cells to various doses
of IL-2 or IL-15. They respond to low-concentrations of cytokines because they express highaffinity (Kd; ~50pM) IL-2 and IL-15 receptors. Importantly, when a cytokine doses pass over
half-saturation concentration (which is equal to the Kd value), cellular responses are no longer
linear to the increase of the dose of the cytokine. When the saturating doses of IL-2 and IL-15
were combined, they no longer create a response over that attained by either cytokine (1+1=1 in
this non-linear world). Inversion of the equation (1-1=1) illustrates neutralization efforts on only
one of the two cytokines (leaving the other cytokine at a saturation dose) which leads to almost
zero inhibition of the cellular response. The other side of the coin is that an antibody to a
cytokine may fail in vivo to show any visible inhibition even thought the target cytokine is
relevantly involved in the activation of the target cell. This observation quite often misleads us
into a conclusion that "the cytokine we studied was not involved in the pathogenic activation".
On the right shown is an actual experimental result that we conducted in support of our argument.
Note that the same dose of anti-IL-2 (or anti-IL-15) mAb effectively neutralized the single target
cytokine, but shows negligible effect when two cytokines are combined (the third group from
left).
Copyright 2017 KEI Journals. All Rights Reserved
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
2-c. Technical limitations of the
current
anti-cytokine
therapy;
as
demonstrated above, monotherapy may not
only be rather ineffective but also the failure
of it may mislead the researchers to a wrong
conclusion when dealing with multiplecytokine diseases. It is particularly true for
cytokine diseases because of the unique
nature of the cytokine that most of them
belong to families and have multiple
siblings/relatives
sharing
biological
functions. So what about combining
antibodies (the most preferred modality in
anti-cytokine therapy) to neutralizing
multiple cytokines? This is very simple
with in vitro experiments, though we wish to
point out that a random combination of
antibodies may be a waste of resource,
energy and time so that one has to build up a
rational strategy before proceeding to the
execution. However, a clinical application
of combinatorial use of antibodies for
therapeutic purposes seems infeasible, due
to the expensive nature of the antibody
therapy. The goal can still be attained by
using other modalities than antibodies. We
will discuss it below.
3. Rational approach to design
multi-cytokine inhibitors
We will start from a general
discussion on how to rationally design a
cytokine intervention, and shift the emphasis
to γc-cytokines which are of our interest.
3-a. Targeting the ligand (cytokine).
As shown above in Figure 1, there are
multiple-levels of targets when intercepting
cytokine function. Neutralizing antibodies
are available for most cytokines. However,
as discussed above, a monoclonal anticytokine antibody (mAb) is not suited for
treating multi-cytokine diseases, unless the
antibody is bispecific (58). However,
generating a bispecific antibody is a
Copyright 2017 KEI Journals. All Rights Reserved
laborious work and is still in the early
developmental stage for clinical applications.
3-b-1. Targeting a shared receptor
component. The next level target is the
cytokine receptor. More to the point, the aim
is targeting the shared receptor
component. Many cytokines share receptor
components with other cytokines due to
their evolution through gene duplication.
This goal can be accomplished in general by
using anti-cytokine receptor antibodies
against the shared component. A soluble
version of the shared receptor component
can be used as well. Alternatively, a ligand
analog that lacks agonistic function
(antagonistic cytokine mimetics, (59)) can
be a potent inhibitor. With the γc-cytokines,
however, no neutralizing anti-γc antibody
exists. This is perhaps because the binding
surface of the γc is highly structurally
conserved across species so the production
of antibodies recognizing this portion may
be blocked by the immune tolerance
mechanism. As mentioned above, IL-2 and
IL-15 share another signaling receptor
subunit, IL-2R/IL-15Rβ (CD122). Heterodimerization of γc and β are needed for
signal transduction by IL-2 or IL-15 (60) so
inhibiting the β-cytokine interaction can
block the signaling triggered by IL-2 or
IL-15. There exist a few neutralizing anti-β
antibodies including Mikβ1 (61).
The
humanized Mikβ1 has been tested in clinical
trials involving T-cell large granular
lymphocyte(LGL)-leukemia
(62)
and
proposed for a diverse array of disorders
including Celiac disease and other
autoimmunity in which IL-2 and IL-15
might allegedly be pathogenic. Nevertheless,
there is a setback for this antibody as well.
However, we need to know a little more
about the dual mode of IL-15 receptor
configuration in order to understand this
issue.
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
3-b-2. The trans- and cis-mode of
IL-15 action. As mentioned above, the β/γc
hetero-dimer is the functional core of the
IL-2/IL-15 receptor, However, these two are
not sufficient for the "in vivo" function of
these cytokines because they only bind
target cytokines at relatively low affinity
(Kd; 0.7 nM) and thus unable to bind them
at their physiological concentrations
(10~100 pM). For the IL-2, a ligand-specific
component IL-2Rα (CD25) joins and
converts the β/γc receptor complex to a
high-affinity IL-2 receptor (Kd; 10 pM). The
in vivo functional IL-2R assumes an IL-2Rα
-IL-2R/IL-15Rβ-γc hetero-trimeric configuration. However, IL-15R is structurally
different. Like the IL-2Rα (CD25), there is
an IL-15-specific binding partner called IL15Rα. However, this molecule behaves as a
component of a hetero-dimeric single
cytokine (like IL-12 and its siblings) which
consists of a complex of IL-15 and IL-15Rα
(hence calling the latter molecule "a
receptor" may not be entirely accurate
though it is a binding protein to IL-15) (6365). They can be formed as a membranebound form on activated dendritic cells
(DCs) and monocytes and then be presented
in trans to T or NK cells which only
expresses the β-γc molecules (the transpresentation mechanism, originally shown
by us and validated by others (63-83).
Several lines of studies indicated that this is
the major physiologic form of IL-15 in vivo.
In other words, the β-γc complex expressed
on the surface of resting T or NK cells in the
absence of IL-2Rα/CD25, is a natural
receptor for IL-15 which can be brought to
T/NK cells by monocytes or dendritic cells
expressing the IL-15/IL-15Rα complexes on
the surface. IL-15Rα can be induced on the
surface of T/NK cells and converts the β-γc
complex to respond to soluble IL-15
monomer (IL-15R in the cis-configuration),
but we have observed that CD8 T cells
constitutively expressing IL-15Rα are more
Copyright 2017 KEI Journals. All Rights Reserved
prone to developing into leukemia (84), a
plausible reason why the trans-configuration
of the IL-15R might be preferred by nature.
Now let us go back to the issue of cytokineneutralizing anti-IL-2R/IL-15Rβ antibody.
The setback is that the Mikβ1 mAb only
effectively blocks the action of IL-2 or
IL-15 when the private α is not present on
the same cells that express the β/γ. This
means IL-2 signaling in vivo cannot be
efficiently blocked by this antibody (since
the only physiological IL-2R consists of all
3 chains expressed by the same cell).
Interestingly, the trans-action of IL-15 can
be efficiently blocked by Mikβ1, but the cisaction is not (62). As we and others have
indicated in the past, trans-IL-15 action is
preferred upon normal immune responses,
therefore Mikβ1 is effective in blocking
such IL-15 actions in vivo. However,
pathologic IL-15 action such as the one seen
with CD8 T-cell leukemia seems to require
the cis-IL-15R configuration by target cells
(84) and the Mikβ1 mAb cannot effectively
block this. Thus, Mikβ1 may have
limitations for blocking IL-2, IL-15 or both
under disease conditions.
3-b-3. Cytokine mimetics. The
cytokine-mimetics are recent developments.
These are fragments from a cytokine or
mutated cytokines with altered functions.
Small peptides containing the active site
(one that is used for interacting with
receptor subunit) of cytokines can mimic the
cytokine action and trigger a signal (agnostic
mimetics). Alternatively, they can block the
active binding site on the cytokine receptor
and inhibit the action of cytokines
(antagonistic mimetics). For therapeutic
purposes, antagonistic mimetics are perhaps
more beneficial. Examples include IL-4
mimetics (85) which have been tested in
clinical trials targeting Asthma with limited
success (86, 87). Importantly, an IL-4
mutant (tyrosine at residue 124 mutated to
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
aspartic acid, Y124D) which has good
binding affinity to IL-4Rα with no signaling
capability can block both IL-4 and IL-13
actions due to the sharing of IL-4Rα
between these two cytokines (88). In a way,
this IL-4 mutant (hIL-4Y124D) is a
prototype
multi-cytokine
inhibitor.
Agonistic cytokine mimetics have been
tested to substitute the cytokine, but they are
not the major focus for this review.
Examples include those for erythropoietin
(89), thrombopoietin (90, 91), interferon
(92), TGF-β (93), hepatocyte growth factor
(94), and chemokines (95), which are being
tested in clinical applications. Our BNZ
peptides (BNZ-1~3) belong to antagonistic
small-molecule γc-cytokine mimetics.
3-b-4 Soluble receptors. There have
been attempts to generate soluble cytokine
receptors for therapeutic purposes (96).
Because soluble cytokine receptors lack the
signal transducing elements, but still bind to
the cytokine with similar affinity as do
membrane-bound counterparts, they can
compete
with the
membrane-bound
receptors for the cytokine binding and
function as inhibitors. Related to the γccytokine world, soluble IL-4R presents an
intriguing example of multi-cytokine
inhibition, as it blocks both IL-4 and IL-13
actions due to the IL-4Rα sharing between
IL-4 and IL-13 as mentioned above (88, 97).
Though IL-13 is not a γc-cytokine, IL-4 and
IL-13 form a subfamily of their own, which
has been implicated in Asthma. Thus,
modalities (e.g., antibodies, mutant IL-4,
and soluble IL-4R) neutralizing these
cytokines have been tested in clinical trials
with some success (47, 48, 98). However,
only monotherapy targeting each cytokine
has been tested so it is not yet clear if a coinhibition of IL-4 and IL-13 has superior
therapeutic effects to those attained by the
single cytokine targeting.
Copyright 2017 KEI Journals. All Rights Reserved
3-c. Targeting Signaling molecules.
Another class of targets for intervening
cytokine action includes signaling molecules.
Unlike many hormone receptors (e.g., those
for insulin, EGF, and Growth Hormones),
cytokine receptor molecules generally lack
an intrinsic kinase activity. Instead,
members of the Janus kinase family (Jak1,
Jak2, Jak3, and Tyk2, reviewed in (99))
specifically interact with cytokine receptors
and help transducing the signal. The
membrane proximal events are probably
easier to target because this is where the
entire cascade of cytokine signaling
becomes convergent. In particular, the γccytokine family presents a unique case
because not only all γc-cytokines use Jak3,
but also the Jak3 usage seems exclusively
limited to γc-cytokines (100-107). This is
underscored by the observation that Jak3
knockout mice (108) or humans with lossof-function Jak3 mutations (105) show
identical phenotypes to γc-knockout mice
(20, 109) or humans with defective γcmolecule (X-linked SCID, (110)). A brilliant
idea was proposed by John O'shea's group,
based on their own discovery of Jak3 and of
its exclusive use by γc-cytokines, to target
Jak3 for blocking actions by a single or
multiple γc-cytokines, and they developed a
Jak3 inhibitor (CP690, 550 (111)) in
collaboration with Pfizer for this purpose.
The compound has been approved by the
FDA as a clinical drug 'Tofacitinib' (29, 84,
112-120). Currently Tofacitinib is being
tested in clinical trials for the treatment of
rheumatoid arthritis (114), graft-versus-host
diseases
associated
with
organ
transplantation (111, 115, 119), inflammatory bowel disease/celiac disease (117, 120)
and T-cell leukemia/lymphoma (22, 29, 84).
We will further evaluate the efficacy and
shortcomings of Tofacitinib as a clinical
drug below.
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Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
4. Can we selectively target multiple
γc-cytokines?
4-a. Safety concerns for the Jak3
inhibitor. So a question may arise as to why
we needed to develop a new technology to
block multiple γc-cytokines? Why are we
not satisfied with the Jak3 inhibitor(s)?
Here is our answer: though a Jak3 inhibitor
would comprehensively block γc-cytokines,
it does not allow us to selectively choose the
target cytokine(s). What we want was to
specifically choose target cytokines within
the γc-family and block only them, but not
other cytokines. In addition, it became clear
that the inhibition by Tofacitinib is not
limited to Jak3 (121) because it inhibits the
kinase activity of Jak2 and Jak1 at high
concentrations (122). Since Jak2 is critically
involved
in
erythropoiesis
and
thrombopoiesis, a continued use of
Tofacitinib might induce anemia and
bleeding tendency (118, 123-126). Other
concerns also cropped up as represented by
the action of the European Commission
which initially declined to approve
Tofacitinib citrate (Xeljanz) for treating
rheumatoid arthritis due to potential
carcinogenesis, mutagenesis and infertility
observed in animal studies. Eventually, it
was recently approved in Europe as well,
and there are on-going efforts to develop
purely-Jak3 specific inhibitors (127) which
will undoubtedly improve the safety of this
strategy. The use of Jak3 inhibitor as a
clinical drug will thus keep advancing.
Nevertheless, we saw in our own hands that
its clinical application may require further
sophistication of the technology. First,
Tofacitinib is a very potent inhibitor to all
γc-cytokine in vitro. However, it does not
seem to show similarly potent inhibitory
effects in vivo. In our mouse model of
IL-15-induced leukemogenesis in which the
continued production of IL-15 by
Copyright 2017 KEI Journals. All Rights Reserved
transgenesis leads to the development of
CD8 T cell leukemia, anti-IL-15 modalities
such as neutralizing mAb to IL-15 or mAb
to IL-2R/IL-15Rβ perfectly protected those
mice from leukemic death (22, 29, 84). So
did BNZ 132-1 (22). Tofacitinib was
administered using subcutaneous pump, but
failed to protect host mice from leukemic
death, only prolonged their survival (22, 29,
84). This may be due to the hydrophobic
chemical nature of Tofacitinib, which makes
it difficult to maintain the compound at
effective dose all the time in vivo.
Furthermore, the strategy of blocking Jak3
kinase itself may present another setback,
because it blocks IL-7. IL-7 is a uniquely
important member of the γc-family because
IL-7 broadly maintains the homeostasis and
development of multiple lymphocyte
lineages. Genetic perturbations or defects of
the IL-7/IL-7R system lead to a profound
loss of T and B cells in mice (9, 128), or a
loss of T cells in humans (129). Normal
numbers of B cells are present in the
absence of the IL-7 signaling in human
neonates, but a further study indicated that
these individuals will develop B-cell
dysfunction later in life (130). Thus, the
impact of IL-7/IL-7R dysfunction is almost
close to that of the loss of γc function itself
in magnitude (SCID in mice (20, 109), and
X-linked SCID in humans (110)). The only
difference in IL-7- and γc-dysfunctions is
the presence or absence of NK cells which
are exclusively maintained by IL-15 (5, 131).
These studies suggest that blocking IL-7 for
a continued period of time may invite
unfavorable outcomes as it could create
severe immune suppression. We propose
that a prolonged inhibition of IL-7 for
therapeutic purposes should be avoided or
kept at a minimum, unless IL-7 itself is the
cause of the disease as reported in subgroups
of T-cell or B-cell acute lymphocytic
leukemia (T-ALL/B-ALL) (132, 133).
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A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
Alignment was performed using the Clustal Omega algorism by the EMBL-EBI (151). The
consensus sequence (A) contains many amino acids that participate in direct physical contact
between the cytokine and γc-molecule, providing evidence that the sequence conservation is
underscored by a structural reason.
Thus, we saw a need to develop a new
technology to block IL-2 and IL-15 (or other
combinations of multiple γc-cytokines,
except IL-7) using a single agent. In a way,
we tried to "shoot many γc-cytokines by a
single stone with a precise target guidance
system". We hypothesized that such
blocking is possible by interrupting the
interaction of γc-cytokines and the shared γc
subunit. Though all γc-cytokines use a broad
overlapping interface, there should be minor
spots that are only occupied by select γccytokines, but not by others. By targeting
such unique spots, we should block select
γc-cytokine combinations.
4-b. The BNZ technology. The past
two decades have seen a tremendous
advancement in our structural knowledge on
the interaction between cytokines and
Copyright 2017 KEI Journals. All Rights Reserved
receptors, owing to dedicated works by
structural biologists. The IL-2/IL-15R
system was no exception. The Garcia group
(Stanford University) has conducted
extensive studies on these receptor systems
and mapped the amino acid residues by
which various cytokines interact with their
receptors. They have also delineated the
binding interface utilized by IL-2 or IL-15
when they are binding to the γc-molecule
(134-139). These studies taught us that the
D-helix (the last of the four helical bundles,
a structure shared by many cytokine
molecules) of the γc-cytokines primarily
interacts physically with the γc-subunit.
Naturally, it makes sense that D-helix is the
most conserved among the all four a-helices
of a γc-cytokine across species (degree of
similarities, D helix>B>A>C (22)). We
noticed a moderately conserved motif
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A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
(which we named "the γc-box", (22)) in this
region of 6-γc cytokines from many species
(Figure 3A). We thus hypothesized that a
peptide which mimics the sequence (and
hence the 3D structure) of this region of γccytokines may have the capacity to inhibit
multiple γc-cytokines. Since the amino acid
sequences of the D-helices are moderately
conserved, we hypothesized it would be
possible to design a peptide which only
resembles IL-2/IL-15, but not IL-4, -7, -9, or
-21. However, this was not a simple task.
We
first
synthesized
a
peptide
corresponding to the D-helix of the human
IL-15 protein, hoping this might be a
specific inhibitor to IL-15, but not to other
γc-cytokines. This peptide did not inhibit
IL-15 (determined by the inhibition of the
T/NK cell proliferation in vitro) (Figure 4).
It later turned out that the IL-15's D-helix
peptide has a very weak binding affinity to
the γc so that it was easily competed off
from the binding pocket by the natural
ligand. We learned from this failure that we
have to leverage the affinity of the peptideγc interaction and specificity of the peptide
in interfering with the binding of each
cytokine to γc. So, we first carefully
examined the published structural data
concerning the binding of IL-15 to γc (138).
This study identified several crucial amino
acids of the D-helix of IL-2 and IL-15 which
form the binding interface with the γc. We
made these amino acids as the "backbone
frame" of our peptides to ensure stable and
tight binding of the peptides to the γc. We
then compared the sequences of IL-2 and
IL-15 across species and generated "a
consensus sequence" which consists of
"conserved" and "wobble (variable)"
positions (Figure 3B, (22)). To the wobble
positions, we assigned amino acids based on
Copyright 2017 KEI Journals. All Rights Reserved
the usages by mammalian IL-2 and IL-15
molecules. We then ran rigorous computer
docking simulation to rule out peptides that
would not stably bind to the γc at the
predicted binding surface. We then
synthesized over 30 peptides which passed
the computer testing and examined their
inhibitory nature using a specific bioassay
and came up with the BNZ 132-1 peptide (a
19-mer synthetic peptide with the sequence
of "IKEFLQRFIHIVQSIINTS", (22, 30)).
5. Proof-of-concept of the BNZ
technology
As shown in our recent publication,
BNZ132-1 peptide efficiently blocks the in
vitro function of IL-2 and IL-15 and to a
lesser extent IL-9 as well (22, 30). We note
that BNZ 132-1 has tight target specificity
as it does not inhibit other γc-cytokines (e.g.,
IL-4, IL-7, IL-21) or non-γc cytokines (22).
Our analysis indicated that the major
signaling pathways downstream of the IL2/IL-15/IL-9R are equally and completely
blocked by BNZ 132-1 (22). To our
knowledge this is the first example of a short
peptide which blocks more than two
cytokines from a family. We extended this
technology to generate additional novel
antagonistic cytokine mimetics which inhibit
IL-15 and IL-21 (BNZ 132-2) and IL-4 and
IL-9 (BNZ 132-3). It is also noteworthy that
BNZ technology generates multi-cytokine
inhibiting
cytokine-mimetics
without
targeting IL-7, as we can exclude peptides
which block IL-7 during the biological
selection process. Though not yet published,
we confirmed that BNZ 132-2, our second
antagonistic mimetic peptide which blocks
IL-15 and IL-21, does not block IL-7
function.
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A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
We first conducted a simple experiment to test our initial hypothesis that the D-helix peptide can
be an antagonistic cytokine-mimetic agent. We ran a docking simulation (PatchDock algorism,
(152, 153)) which predicted that this peptide does not form stable binding with the γc-molecule
at the reported cytokine binding interface of this molecule (22). This highly suggests that the
peptide may not work as an antagonist to γc-cytokines. We then conducted a biological assay in
which we incubated mitogen-activated human T cells with low doses of γc-cytokines (IL-2; 50
pM, IL-15; 50 pM, IL-21; 10 pM) to induce tyrosine-phosphorylation of signaling molecules
including STAT1, STAT3 and Erk1/2 as shown in the figure. We saw no inhibition of STAT1
and Erk1/2 which are signature signaling evens associated with IL-15 activation of Tlymphocytes. The signaling by IL-2 or IL-21 was not inhibited, either. This experiment taught us
that the D-helix sequence needs to be optimized so that the peptide functions as an antagonist by
competitively inhibiting the binding of target cytokines to the γc-molecule at the right interface.
6. Target diseases for the BNZ
technology
When we chose IL-2 and IL-15 as the
target and started designing the inhibitory
peptide, we already had in mind that such a
peptide can be used for treating HAM/TSP
caused by human T-cell leukemia virus-1
(HTLV-1) (23, 24). The constitutive in vivo
activation of T-lymphocytes in HAM/TSP
patients is initiated by the Tax-1 protein
(140) of this virus and maintained by the
combination of IL-2 and IL-15 produced as
a consequence of HTLV-1 activation of
CD4 T cells as we and others have
previously demonstrated (25-28, 45, 141). In
Copyright 2017 KEI Journals. All Rights Reserved
addition to IL-2 and IL-15, a recent report
suggests that the IL-9/IL-9R system is also
playing a pertinent role in this disease (142).
Incidentally, IL-9 is another target of BNZ
132-1 which was not originally anticipated
by us when we designed BNZ132-1. As
shown in our recent publication, BNZ132-1
alone can very efficiently block the
spontaneous proliferation of T cells from
multiple
HAM/TSP
patients
(30).
Furthermore, BNZ 132-1 also downregulated various hallmark activation events
associated with HAM/TSP T cells, including
the tyrosine-phosphorylation of signaling
molecule STAT5, and the survival of
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A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
HTLV-1 specific CD8 T cells (as
determined by a Tax-tetramer staining) (30).
Thus, BNZ 132-1 is a prime candidate by
which to treat HAM/TSP patients. We
expect that the PEGylated form of this
peptide (see below) will stably circulate in
the patients, subside the constitutive
activation of T cells and revert the
lymphokine-activated killer (LAK) cells and
CTLs to resting state so that they will stop
damaging
neuronal
tissues/cells
in
HAM/TSP patients. Subsequent studies
made us convinced, however, that there are
more diseases that can be efficiently treated
by the BNZ 132-1 peptide.
We will
describe our recent progress below.
The IL-15 leukemic cells line was established from the IL-15 Tg mouse (C57B6, CD90.2
background) we generated (6, 84). These cells grow in syngeneic normal mice (C57B6 strains)
and form secondary leukemia upon grafting. Without treatment, the recipient mice will die of
CD8 T cell leukemia within 30 days of the injection of leukemic cells. The graph shows the
preferential expansion of CD90.2+ CD8 leukemic T cells in the CD90.1+ congenic C57B6 mice
as determined by flow cytometry (Black line). The only CD90.2 + cells in these mice are from
grafted IL-15 leukemic cells. Since these leukemic cells are dependent on IL-15 for their growth,
injection of a neutralizing anti-IL-15 mAb (Mab247, R & D Systems, 150 µg /intraperitoneal
injection, twice per week for two weeks) eradicates leukemic cells thus no CD90.2+ leukemic T
cells are found in the blood or spleen of recipient mice (Green line). Treatment by BNZ132-1-40
(PEGylated form, 1 mg/kg per dose, intraperitoneal injections twice per week) shows similar
protective effects (Red line) as anti-IL-15mAb treatment. Curiously, Tofacitinib, infused by a
subcutaneous pump, only delayed the onset of explosive expansion of leukemic cells, but failed
to show a complete remission (Blue line).
7. BNZ 132-1 as a therapeutic drug.
7-a. Stable Pharmacokinetic nature
of BNZ 132-1. Since BNZ 132-1 is a short
(19-mer) peptide, it will quickly be lost from
the body as the result of rapid renal
clearance.
Thus, we tried a few
Copyright 2017 KEI Journals. All Rights Reserved
modifications of the peptide to elongate the
biological half life and PEGylation, a
commonly used modifying technique for
proteins and peptides, to enhance the
pharmacokinetic (PK) properties of the
peptide.
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A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
7-b. Pharmacodynamics of BNZ
132-1; The IL-15 leukemia model as the
proving ground that BNZ 132-1 can be a
therapeutic compound for LGL-type
leukemia in humans.
After the confirmation that the
PEGylated version (BNZ 132-1-40) has
similar in vitro inhibiting activity on IL-2 or
IL-15-geared cellular proliferation as the
original peptide (22), Pharmacokinetics
(PK) and pharmacodynamics (PD) of the
drug were determined using mouse models
of cytokine challenge. The over-expression
of IL-2 leads to the preferential expansion of
CD4
regulatory
T
cells
(T-regs)
+
hi
+
(CD4 CD25 Foxp3 T cells with suppressive function, reviewed in (143, 144)) as we
have previously shown in the IL-2
transgenic (Tg) mouse that we generated (4).
This can be imitated by administering
recombinant human IL-2 into mice.
Likewise, the injection of recombinant IL-15
into mice causes a temporal expansion of
mouse NK cells (84). As reported (22), two
bolus injections of recombinant human IL-2
or human IL-15 (150 µg/shot) led to a
temporal expansion of T-regs or NK cells,
respectively. This transient expansion of Tregs or NK cells were almost completely
blocked by the concomitant administration
of BNZ 132-1-40 (1 mg/kg, two injections
over a week). These experiments convinced
us that BNZ 132-1-40 is stable in vivo and
can be a drug-candidate for humans. PK
studies in the currently on-going phase I-a
clinical trials validated that the T 1/2 of BNZ
132-1-40 is around 72 hr in normal
individuals, thus we could maintain it above
minimum effective dose (0.2~0.4 mg/kg) by
injecting a single dose of 1~2 mg/kg BNZ
132-1-40 over the next 14 days, reaffirming
that BNZ 132-1-40 is a stable compound
suited for clinical use.
Next, we tested the in vivo efficacy of
the PEGylated form of BNZ 132-1 in a
Copyright 2017 KEI Journals. All Rights Reserved
clinically relevant model involving the overproduction of IL-15. We and others had
generated IL-15 transgenic (Tg) mice
previously (6), and observed that they
develop a fatal CD8 T cell leukemia (7, 8,
84). This experimental leukemia resembles
human T-cell malignancies developing from
CD8/LGL cells (7, 8). Using the IL-15
transgenic mouse they generated, the
Caligiuri group (Ohio State University)
demonstrated that this model recapitulates
characteristics associated with human LGL
leukemia and cutaneous T-cell leukemia
(CTCL). In addition, they recently showed
that the epigenetic modification which
occurs at the il15 locus in human LGLleukemia patients can be observed in IL-15
Tg mice as well (145-147). Based on these
observations, they proposed to treat patients
with LGL leukemia and CTCL by anti-IL-15
therapies (147). Likewise, we explored our
IL-15 Tg mouse model to test similar
therapeutic possibility. As reported (84), we
have established leukemic CD8 T cell clones
from our IL-15 Tg mice. These cells can be
expanded in culture without any addition of
cytokines. These leukemic clones are still
dependent on the IL-15 which they produce
because the inclusion of anti-IL-15 antibody
to the culture immediately stops cellular
proliferation and induces apoptotic death
(84). Importantly, these cells can be grafted
into a syngeneic host mouse (the C57B6
strain) and kill the host within 4-6 weeks
time
by
forming
a
secondary
leukemia/lymphoma (29, 84). This model
was used to test if BNZ 132-1 suppresses the
leukemic growth of IL-15-producing CD8
T-cells and protects host mice from
leukemic death. As control and comparison,
anti-IL-15 neutralizing antibody and
Tofacitinib were included in the experiment.
Control mice without any treatment died
within 30 days following the injection of IL15 Tg leukemic cells (K2) as reported before
(29, 84). Anti-IL-15, or anti-mouse ILPage │14
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A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
2R/IL-15Rβ (anti-mouse CD122, TMβ1)
mAb protected mice as expected. BNZ 1321-40 (the PEGylated form), administered
intravenously (IV)) 4 times (on days 1, 4, 8,
and 11 after the injection of leukemic cells)
at 1 mg/kg dose, prevented the mouse as
efficiently
as
anti-cytokine/cytokinereceptor antibodies. Moreover, experiments
were conducted to allow distinguishing
grafted leukemic cells and host lymphocytes
by congenic markers (i.e., leukemic cells are
from CD90.2 C57B6 mice whereas the
recipient mice are CD90.1 C57B6). A
thorough flow-cytometric examination of
the blood and secondary lymphoid organs
revealed that there were no traceable
CD90.2+ leukemic cells remaining in host
mice after the BNZ132-1-40 treatment.
Autopsy and histological analyses validated
the assessment. These data strongly suggest
that
BNZ132-1-40
has
completely
eradicated IL-15-dependent CD8 leukemic T
cells from leukemic mice. Curiously,
Tofacitinib, which was administered using a
cutaneous pump showed only marginal
therapeutic effects as described above
(22, 29). These results suggest that BNZ1321-40 may be a superior "in vivo blocker" of
IL-2 or IL-15 than Tofacitinib.
subsets was observed following a single
administration of BNZ 132-1-40 (0.2, 0.4,
0.8, 1.6, 3.2 and 6.4 mg/kg). The detailed
results will be published elsewhere in the
near future (manuscript in preparation). To
apply BNZ132-1 to wider diseases, studies
are in progress to test if BNZ132-1
effectively suppresses graft-versus-host
(GvH) responses upon transplantation.
Previous studies suggested that this process
involves IL-15, but not IL-2 (148-150).
However, in our experimental system we
saw that only co-inhibition of IL-2 and IL15 (by combining anti-IL-2 and anti-IL-15
antibodies, or by BNZ132-1-40), but not the
blockade of a single cytokine, ameliorated
the GvH symptoms (manuscript in
preparation). This represents another
compelling example in which monotherapy
(targeting a single cytokine) fails to display
therapeutic effects and multi-cytokine
inhibition is needed for attaining the goal.
Thus, we are continuing our efforts to obtain
additional IND approvals on BNZ132-1 for
treating other hematologic and immunologic
diseases including GvH disease and
autoimmunity.
7-c. IND approval and on-going
clinical trials involving BNZ132-1. As
described above, BNZ132-1 has received an
IND approval from the FDA to conduct a
phase I-a clinical trial targeting normal
volunteers to evaluate its drug candidacy. In
preclinical studies that we conducted before
an IND submission, we saw reduction of NK
and some other types of T cells in the mice
and in the cynomologus macaques, as
expected based on the known homeostatic
roles of IL-15 to maintain these cells and
those of IL-2 on T-regs, respectively. In the
Phase I-a clinical trial that has just been
completed, a significant decrease of NK
cells and of other relevant lymphocyte
Years ago, we observed that the ex
vivo spontaneous proliferation of HAM/TSP
T cells which is driven by a combination of
almost equal amounts of IL-2 and IL-15
cannot be efficiently blocked by a single
neutralizing mAb either to IL-2 or IL-15.
This contrasted with our intuitive prediction
in which we expected to see a near 50%
neutralization by the individual antibody,
which made us realize the fraud in our logic
and a related gap in the existing anticytokine approach, and triggered subsequent
research to develop a new tool (multicytokine inhibitor) that we have now. Our
recent publications represent the proof-ofconcept of our novel technology to
rationally design multi-cytokine inhibitors.
Copyright 2017 KEI Journals. All Rights Reserved
Summary
Page │15
Medical Research Archives, Vol. 5, Issue 9, September 2017
A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
Our research shows that an increasing
number of human diseases may be
efficiently treated by our multi-cytokine
inhibitors (MCIs). Currently our compounds
are still limited to blocking the γc-family
cytokines, but we plan to develop new class
of inhibitors that block cytokines belonging
to different cytokine families..
Acknowledgements
The authors thank for the help
received from members of the Tagaya lab
(Marco Goicochea, Juan C. Zapata, Rick
van Besien, Toshie Nata, Fiorenza Cocchi,
Xiaorong Wu and Eugene Ateh) and the
research lab at BIONIZ therapeutics (Asjad
Basheer, and Nick Doerr) who have
Copyright 2017 KEI Journals. All Rights Reserved
contributed, but not been included as authors
of this article. We declare no financial
conflicts of interests.
This work was
supported by internal funds from the
Institute of Human Virology at the
University of Maryland School of Medicine,
and funds from BIONIZ therapeutics, Irvine,
CA.
BNZ 132-1 and other BNZ peptides
were protected by the US patent (08455449)
and owned by the BIONIZ therapeutics.
Animal experiments were conducted
at the BioQual Inc. (Rockville, MD) under
protocols approved by the IACUC
committee.
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A novel therapeutic strategy targeting multiple members of the γc-family cytokines;
principles, relevance and potentially broad clinical applications.
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